Abstract
Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
Highlights
NTHL1 encodes a DNA glycosylase that is a critical component of the DNA base excision repair (BER) pathway involved in the repair of oxidatively damaged DNA
It has recently been shown that carriers of bi-allelic loss-of-function (LoF) variants in NTHL1 are predisposed to colorectal adenomatous polyposis and colorectal cancer[1], and to a multi-tumor syndrome that includes a high incidence of breast cancer in female carriers[2,3,4,5]
NTHL1 is a DNA glycosylase involved in the earliest steps of the repair of oxidative DNA damage through the BER pathway
Summary
NTHL1 encodes a DNA glycosylase that is a critical component of the DNA base excision repair (BER) pathway involved in the repair of oxidatively damaged DNA. It has recently been shown that carriers of bi-allelic loss-of-function (LoF) variants in NTHL1 are predisposed to colorectal adenomatous polyposis and colorectal cancer[1], and to a multi-tumor syndrome that includes a high incidence of breast cancer in female carriers[2,3,4,5]. Grolleman et al.[4] described the largest set of carriers of bi-allelic germline NTHL1 variants (29 carriers from 17 families), and reported that 9 of 15 female carriers (60%) were diagnosed with breast cancer at an earlier age than observed in the general population Published in partnership with the Breast Cancer Research Foundation N. Exon (of 6) dbSNP ID GnomADc Frameshift Stop Gained 25d Stop Gained
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